Drug-induced narrowing of the width of the zone of entrainment as a predictor of the subsequent non-inducibility of reentrant ventricular tachycardia after an additional dose of an antiarrhythmic drug.
The efficacy of drugs used to treat inducible monomorphic sustained ventricular tachycardia (VT) has been assessed by investigating their ability to suppress inducibility, but the mechanism of the drug action remains to be determined. To determine electrophysiological variables that predict inducibility, divided doses of class I antiarrhythmic drugs were given and their effects were analysed, particularly the ability of the final dose to suppress inducibility. The excitable gap was estimated by the zone of entrainment, which was defined as the difference between the cycle length of VT and the longest paced cycle length that interrupted VT during entrainment of VT with rapid pacing at paced cycle lengths in decrements of 10 ms. The cycle length of VT, the block cycle length, and the zone of entrainment were measured in the drug free state and after intermediate and final doses of procainamide, disopyramide, cibenzoline, and mexiletine. Sustained monomorphic VT with a mean (SD) cycle length of 285 (43) ms was induced in 8 patients. It was entrained and interrupted at the block cycle length of 231 (31) ms. The width of the zone of entrainment was 54 (23) ms. In 8 studies VT was not inducible at final doses of procainamide in 4, cibenzoline in 1, and mexiletine in 3. In another 10 studies (procainamide in 4, disopyramide in 1, cibenzoline in 2, and mexiletine in 3), VT remained inducible at the intermediate dose and at the final dose. The cycle length of VT was prolonged to a similar degree in studies of effective and ineffective drugs, but the cycle length that blocked VT was longer at the intermediate dose of the effective drugs. Consequently, the width of the zone of entrainment was significantly narrowed at the intermediate dose of effective drugs and the width of the zone of entrainment was narrower than when ineffective drugs were given (22 (13) ms v 76 (18) or 75 (37) ms at the intermediate and final doses respectively (P < 0.02). Drugs that narrowed the zone of entrainment were associated with non-inducibility of VT after the final dose of the drug was given. The baseline variables did not predict the responses to class I antiarrhythmic drugs.


Emergency Department Visits by Adolescent and Young Adult Cancer Patients Compared with Pediatric Cancer Patients in the United States.
Limited information exists on emergency department (ED) visits for adolescent and young adult (AYA) patients with cancer. We examined the clinical reasons for ED visits, and outcomes, for AYAs with cancer compared to pediatric cancer patients. The 2013 Nationwide Emergency Department Sample data were used to identify 53,274 AYA (ages 15-39) and 6952 pediatric (ages 0-14) cancer ED visits. We evaluated patient (i.e., demographic and diagnosis) and hospital characteristics, and the ED event outcome (admitted to the same hospital or treated/released). Clinical reasons for visits were identified as procedures, infections, or noninfectious toxicities. Variables were compared between groups using chi-squared tests. Logistic regressions identified characteristics associated with the outcome between and within groups. AYA cancer visits were more likely to be self-paid (15.8% vs. 1.9%, p < 0.001), and be from low-income households and nonmetro counties than pediatric visits. Toxicity was the most prevalent reason for AYA visits (46.0%) and infections for pediatrics (47.3%, p < 0.001). AYA cancer visits were less likely to be admitted (OR = 0.84, 95% CI = 0.71-0.98; p = 0.03) than pediatric cancer. Among AYAs, self-paid visits were less likely to be admitted compared with privately insured visits (OR = 0.58, 95% CI: 0.52-0.66, p < 0.001). Self-pay did not affect the outcome for pediatric visits. In the United States, compared with pediatric cancer patients, AYAs with cancer visit EDs more often for toxicity-related problems, and are more often self-paid and from poorer households. These distinctive features impacting health service use should be incorporated into care plans aimed at delineating effective care for these patients.


A population study of the long-term consequences of Rose angina: 20-year follow-up of the Renfrew-Paisley study.
To examine the long-term cardiovascular consequences of angina in a large epidemiological study. Prospective cohort study conducted between 1972 and 1976 with 20 years of follow-up (the Renfrew-Paisley Study). Renfrew and Paisley, West Scotland, UK. 7048 men and 8354 women aged 45-64 years who underwent comprehensive cardiovascular screening at baseline, including the Rose Angina Questionnaire and electrocardiography (ECG). All deaths and hospitalisations for cardiovascular reasons occurring over the subsequent 20 years, according to the baseline Rose angina score and baseline ECG. At baseline, 669 (9.5%) men and 799 (9.6%) women had angina on Rose Angina Questionnaire. All-cause mortality for those with Rose angina was 67.7% in men and 43.3% in women at 20 years compared with 45.4% and 30.4%, respectively, in those without angina (p<0.001). Values are expressed as hazards ratio (HR) (95% confidence interval (CI). In a multivariate analysis, men with Rose angina had an increased risk of cardiovascular death or hospitalisation (1.49 (1.33 to 1.66), myocardial infarction (1.63 (1.41 to 1.85)) or heart failure (1.54 (1.13 to 2.10)) compared with men without angina. The corresponding HR (95% CI) for women were 1.38 (1.23 to 1.55), 1.56 (1.31 to 1.85) and 1.92 (1.44 to 2.56). An abnormality on the electrocardiogram (ECG) increased risk further, and both angina and an abnormality on the ECG increased risk most of all compared with those with neither angina nor ischaemic changes on the ECG. Compared with men, women with Rose angina were less likely to have a cardiovascular event (0.54 (0.46 to 0.64)) or myocardial infarction (0.44 (0.35 to 0.56)), although there was no sex difference in the risk of stroke (1.11 (0.75 to 1.65)), atrial fibrillation (0.84 (0.38 to 1.87)) or heart failure (0.79 (0.51 to 1.21)). Angina in middle age substantially increases the risk of death, myocardial infarction, heart failure and other cardiovascular events.


Evaluation of the Structure-Function Relationship in Glaucoma Using a Novel Method for Estimating the Number of Retinal Ganglion Cells in the Human Retina.
We developed a simple method for estimating the number of retinal ganglion cells (RGCs) in the human retina using optical coherence tomography (OCT), compared it to a previous approach, and demonstrated its potential for furthering our understanding of the structure-function relationship in glaucoma. Swept-source (ss) OCT data and 10-2 visual fields (VFs) were obtained from 43 eyes of 36 healthy controls, and 50 eyes of 50 glaucoma patients and suspects. Using estimates of RGC density from the literature and relatively few assumptions, estimates of the number of RGCs in the macula were obtained based on ssOCT-derived RGC layer thickness measurements. The RGC estimates were in general agreement with previously published values derived from histology, whereas a prior method based on VF sensitivity did not agree as well with histological data and had significantly higher (P = 0.001) and more variable (P < 0.001) RGC estimates than the new method based on ssOCT. However, the RGC estimates of the new approach were not zero for extreme VF losses, suggesting that a residual, non-RGC contribution needs to be added. Finally, the new ssOCT-derived RGC estimates were significantly (P < 0.001 to P = 0.018) related to VF sensitivity (Spearman's ρ = 0.26-0.47), and, in contrast to claims made in prior studies, statistically significant RGC loss did not occur more often than statistically significant visual loss. The novel method for estimating RGCs yields values that are closer to histological estimates than prior methods, while relying on considerably fewer assumptions. Although the value added for clinical applications is yet to be determined, this approach is useful for assessing the structure-function relationship in glaucoma.


Assessment of Culicoides barbosai as a vector of Mansonella ozzardi in Haiti.
Studies in the southern peninsula of Haiti showed that the biting midge, Culicoides barbosai, was capable of supporting the development of Mansonella ozzardi to the infective stage. The known vector, Culicoides furens, also was encountered. Both species showed distinct biting site preferences, i.e., 98% of the midges that engorged on the arms and head were C. barbosai whereas C. furens was collected mostly from the lower legs. Nine days after engorgement, 19 infective larvae were recovered from 13 C. barbosai versus six larvae from four C. furens. It was judged that C. barbosai may be as importantly involved in the natural transmission cycle as C. furens in this community.


Side-binding proteins modulate actin filament dynamics.
Actin filament dynamics govern many key physiological processes from cell motility to tissue morphogenesis. A central feature of actin dynamics is the capacity of filaments to polymerize and depolymerize at their ends in response to cellular conditions. It is currently thought that filament kinetics can be described by a single rate constant for each end. In this study, using direct visualization of single actin filament elongation, we show that actin polymerization kinetics at both filament ends are strongly influenced by the binding of proteins to the lateral filament surface. We also show that the pointed-end has a non-elongating state that dominates the observed filament kinetic asymmetry. Estimates of flexibility as well as effects on fragmentation and growth suggest that the observed kinetic diversity arises from structural alteration. Tuning elongation kinetics by exploiting the malleability of the filament structure may be a ubiquitous mechanism to generate a rich variety of cellular actin dynamics.


Schwann cells transduced with a lentiviral vector encoding Fgf-2 promote motor neuron regeneration following sciatic nerve injury.
Fibroblast growth factor 2 (FGF-2) is a trophic factor expressed by glial cells and different neuronal populations. Addition of FGF-2 to spinal cord and dorsal root ganglia (DRG) explants demonstrated that FGF-2 specifically increases motor neuron axonal growth. To further explore the potential capability of FGF-2 to promote axon regeneration, we produced a lentiviral vector (LV) to overexpress FGF-2 (LV-FGF2) in the injured rat peripheral nerve. Cultured Schwann cells transduced with FGF-2 and added to collagen matrix embedding spinal cord or DRG explants significantly increased motor but not sensory neurite outgrowth. LV-FGF2 was as effective as direct addition of the trophic factor to promote motor axon growth in vitro. Direct injection of LV-FGF2 into the rat sciatic nerve resulted in increased expression of FGF-2, which was localized in the basal lamina of Schwann cells. To investigate the in vivo effect of FGF-2 overexpression on axonal regeneration after nerve injury, Schwann cells transduced with LV-FGF2 were grafted in a silicone tube used to repair the resected rat sciatic nerve. Electrophysiological tests conducted for up to 2 months after injury revealed accelerated and more marked reinnervation of hindlimb muscles in the animals treated with LV-FGF2, with an increase in the number of motor and sensory neurons that reached the distal tibial nerve at the end of follow-up.


Oral Lichenoid Lesion Manifesting as Desquamative Gingivitis: Unlikely Association? Case Report.
The aim of this report is to present a clinical case of oral lichenoid lesions associated with amalgam restorations with the presence of desquamative gingivitis for a nine months follow up period. The histopathologic characteristics and direct immunofluorescence were compatible with Oral Lichenoid Lesion (LLO). Diagnosis was based on a synthesis of all available information, including medical history, clinical examination, histopathology and the results of specific tests, such as the patch test, which confirmed allergy to thimerosal, an organic compound of mercury. The replacement of amalgam restorations has brought improvements to the instrument, as evidenced by the disappearance of desquamative gingivitis, aspect erythematosus and erosive lesions. The fading does not complete the same, however, indicates the need to continue has been under continuous observation, the patient, having in view the possibility of the existence of an underlying lichen planus.


Reciprocal mouse and human limb phenotypes caused by gain- and loss-of-function mutations affecting Lmbr1.
The major locus for dominant preaxial polydactyly in humans has been mapped to 7q36. In mice the dominant Hemimelic extra toes (Hx) and Hammertoe (Hm) mutations map to a homologous chromosomal region and cause similar limb defects. The Lmbr1 gene is entirely within the small critical intervals recently defined for both the mouse and human mutations and is misexpressed at the exact time that the mouse Hx phenotype becomes apparent during limb development. This result suggests that Lmbr1 may underlie preaxial polydactyly in both mice and humans. We have used deletion chromosomes to demonstrate that the dominant mouse and human limb defects arise from gain-of-function mutations and not from haploinsufficiency. Furthermore, we created a loss-of-function mutation in the mouse Lmbr1 gene that causes digit number reduction (oligodactyly) on its own and in trans to a deletion chromosome. The loss of digits that we observed in mice with reduced Lmbr1 activity is in contrast to the gain of digits observed in Hx mice and human polydactyly patients. Our results suggest that the Lmbr1 gene is required for limb formation and that reciprocal changes in levels of Lmbr1 activity can lead to either increases or decreases in the number of digits in the vertebrate limb.


Towards automatic image analysis and assessment of the multicellular apoptosis process.
Apoptotic programmed cell death (PCD) is a fundamental aspect of developmental maturation. However, the authors' understanding of apoptosis, especially in the multi-cell regime, is incomplete because of the difficulty of identifying dying cells by conventional strategies. Real-time in vivo microscopy of Drosophila, an excellent model system for studying the PCD during development, has been used to uncover plausible collective apoptosis at the tissue level, although the dynamic regulation of the process remains to be deciphered. In this work, the authors have developed an image-analysis program that can quantitatively analyse time-lapse microscopy of live tissues undergoing apoptosis with a fluorescent nuclear marker, and subsequently extract the spatiotemporal patterns of multicellular response. The program can process a large number of cells (>103) automatically tracked across sets of image frames. It is applied to characterise the apoptosis of Drosophila wing epithelium at eclosion. Using the natural anatomic structures as reference, the authors identify dynamic patterns in the progression of PCD within the Drosophila tissues. The results not only confirm the previously observed collective multi-cell behaviour from a quantitative perspective, but also reveal a plausible role played by the anatomic structures, such as the wing veins, in the PCD propagation across the Drosophila wing.


Electromagnetic localization based on transformation optics.
Localization of an electromagnetic field can be achieved by transformation optics using metamaterials. A coordinate transformation structure different from traditional resonator is proposed. Wherein, arbitrary frequency of the whole band of electromagnetic wave can be localized without energy loss, i.e., the modes in this structure are continuous. Theoretical analysis and numerical simulation show that the material parameter variations at the outer boundary of the structure have little influence on the localization property. When realizable physical structure is considered, multi-layer approximation should be applied. The calculated results show that the estimated localization time is about 100 ns for an 8-layer inhomogeneous approximation, and it could reach several seconds for a 30-layer homogeneous approximation. The present work may present a new application of transformation optics.


Neuronal Constituents and Putative Interactions Within the Drosophila Ellipsoid Body Neuropil.
The central complex (CX) is a midline-situated collection of neuropil compartments in the arthropod central brain, implicated in higher-order processes such as goal-directed navigation. Here, we provide a systematic genetic-neuroanatomical analysis of the ellipsoid body (EB), a compartment which represents a major afferent portal of the Drosophila CX. The neuropil volume of the EB, along with its prominent input compartment, called the bulb, is subdivided into precisely tessellated domains, distinguishable based on intensity of the global marker DN-cadherin. EB tangential elements (so-called ring neurons), most of which are derived from the DALv2 neuroblast lineage, predominantly interconnect the bulb and EB domains in a topographically organized fashion. Using the DN-cadherin domains as a framework, we first characterized this connectivity by Gal4 driver lines expressed in different DALv2 ring neuron (R-neuron) subclasses. We identified 11 subclasses, 6 of which correspond to previously described projection patterns, and 5 novel patterns. These subclasses both spatially (based on EB innervation pattern) and numerically (cell counts) summate to the total EB volume and R-neuron cell number, suggesting that our compilation of R-neuron subclasses approaches completion. EB columnar elements, as well as non-DALv2 derived extrinsic ring neurons (ExR-neurons), were also incorporated into this anatomical framework. Finally, we addressed the connectivity between R-neurons and their targets, using the anterograde trans-synaptic labeling method, trans-Tango. This study demonstrates putative interactions of R-neuron subclasses and reveals general principles of information flow within the EB network. Our work will facilitate the generation and testing of hypotheses regarding circuit interactions within the EB and the rest of the CX.


Anxiolytic effects of Equisetum arvense Linn. extracts in mice.
The petroleum ether (PE), chloroform (CH), ethanol (ETH) and water extracts of E. arvense stems were evaluated for anti-anxiety activity in mice using elevated plus maze model. Ketamine induced hypnosis and actophotometer was used to evaluate sedative effect with various extracts in mice. The results were compared with standard drug diazepam. The ethanolic extract of E. arvense (50 and 100 mg/kg) significantly increased the time-spent and the percentage of the open arm entries in the elevated plus-maze model which was comparable to diazepam. Ethanolic extract (100 mg/kg) prolonged the ketamine-induced total sleeping time and decreased the locomotor activity in mice. The results suggest that the ethanolic extract of E. arvense seems to possess anxiolytic effect with lower sedative activity than that of diazepam. The results could be attributed to the flavonoid content of the ethanolic extract.


Imaging in cervical cancer.
Cervical cancer traditionally has been staged clinically. Advances in imaging could improve the staging of cervical cancer by facilitating the detection of lymph node metastases and micrometastases in distant organs. Such progress could lead to improvements in treatment selection and therefore increase overall survival rates. At the Second International Conference on Clinical Cancer (Houston, TX, April 11-14, 2002), a panel composed of gynecologic oncologists, radiation oncologists, and diagnostic radiologists reviewed relevant technologies. Advances in lymphangiography, ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and lymphatic mapping were reviewed, along with the impact of these advances on the diagnosis, treatment, and survival of patients with cervical cancer. Few cancer centers still use lymphangiography, but the sensitivity of this method ranges from 28% to 83%, with specificity ranging from 47% to 100%. The roles of transabdominal and transvaginal ultrasonography in evaluating cervical cancer are expected to expand when new contrast agents increase the sensitivity of these techniques to parametrial invasion and lymph node metastases; meanwhile, ultrasonography's most significant contributions may involve the identification of uterine and cervical leiomyomas and the evaluation of urinary tract obstruction. Advances in CT have made it a rival technique to MRI, but limitations prevent CT from providing definitive information on certain parameters. MRI, which is valuable because of its superior soft tissue contrast resolution, multiplanar capabilities, and cost-effectiveness, is used to determine the size of the cervix and to detect certain types of invasion, characteristics of lymph nodes, and the presence of disease in the ureter, lung, and liver. PET with 2-[fluorine-18]fluoro-2-deoxy-D-glucose has been found to detect abnormal lymph node regions better than CT does but PET can also be used in conjunction with CT to measure tumor dimensions. PET also has become a method for identifying tumors that are unresponsive to chemoradiation. When used together with immunohistochemical and molecular techniques as well as conventional stains, sentinel lymph node mapping, an important development in the surgical management of solid tumors, is expected to improve gynecologic cancer management. Advances in imaging methods and in contrast agents, along with advances in the combined use of the two, are expected to make imaging technologies more valuable in cervical cancer assessment.


Endometrial cancer: socioeconomic status and racial/ethnic differences in stage at diagnosis, treatment, and survival.
We evaluated the association between socioeconomic status and racial/ ethnic differences in endometrial cancer stage at diagnosis, treatment, and survival. We conducted a population-based study among 3656 women. Multivariate analyses showed that either race/ethnicity or income, but not both, was associated with advanced-stage disease. Age, stage at diagnosis, and income were independent predictors of hysterectomy. African American ethnicity, increased age, aggressive histology, poor tumor grade, and advanced-stage disease were associated with increased risk for death; higher income and hysterectomy were associated with decreased risk for death. Lower income was associated with advanced-stage disease, lower likelihood of receiving a hysterectomy, and lower rates of survival. Earlier diagnosis and removal of barriers to optimal treatment among lower-socioeconomic status women will diminish racial/ethnic differences in endometrial cancer survival.


Pharmacologic therapies for complex regional pain syndrome.
Complex regional pain syndrome (CRPS) remains a challenging condition to diagnose and treat. There are few large-scale, randomized trials of pharmacologic agents, and most published studies are small, uncontrolled, or presented only in abstract form at meetings. The most commonly used agents, such as anticonvulsants, antidepressants, and opiates, have been found to be useful for other neuropathic pain conditions in large-scale trials but have not been adequately studied in CRPS. Systemic steroids delivered by multiple routes continue to be used, with some good evidence for short-term administration. N-methyl-D-aspartate antagonists have recently gained in popularity, without evidence from well-controlled trials. Bisphosphonates have been well studied and offer promise. In addition, there has been interest in thalidomide; however, we are still awaiting well-controlled trials. This article presents an overview of the available data regarding pharmacologic therapies for CRPS. These agents should be used in conjunction with a comprehensive interdisciplinary approach aimed at functional restoration and improved quality of life.


The Impact of Obesity on the Cardiovascular System.
Obesity is a growing health problem worldwide. It is associated with an increased cardiovascular risk on the one hand of obesity itself and on the other hand of associated medical conditions (hypertension, diabetes, insulin resistance, and sleep apnoea syndrome). Obesity has an important role in atherosclerosis and coronary artery disease. Obesity leads to structural and functional changes of the heart, which causes heart failure. The altered myocardial structure increases the risk of atrial fibrillation and sudden cardiac death. However, obesity also has a protective effect on the clinical outcome of underlying cardiovascular disease, the phenomenon called obesity paradox. The improved cardiac imaging techniques allow the early detection of altered structure and function of the heart in obese patients. In this review, we attempt to summarize the relationship between obesity and cardiovascular diseases and outline the underlying mechanisms. The demonstrated new techniques of cardiac diagnostic procedures allow for the early detection and treatment of subclinical medical conditions and, therefore, the prevention of cardiovascular events.


Potential effects of mercury on threatened California black rails.
San Francisco Bay (SFB) estuary sediments contain high levels of mercury (Hg), and tidal marsh resident species may be vulnerable to Hg contamination. We examined Hg concentrations in California black rails, a threatened waterbird species that inhabits SFB tidal salt marshes. We captured 127 black rails during the prebreeding and postbreeding seasons and examined the influence of site, sex, and year on Hg, methylmercury (MeHg), and also selenium (Se) concentrations in feathers and blood. Feather Hg concentrations averaged 6.94 microg/g dry weight (dw) and MeHg and Se concentrations in blood averaged 0.38 and 0.42 microg/g wet weight (ww). We used Akaike's information criterion model selection process to evaluate the importance of year, site, sex, and age on patterns of MeHg concentrations; sex and year were the most important of these factors. Feather Hg concentrations (dw) were higher in males (8.22 microg/g) than females (6.63 microg/g) and higher in adult birds (7.36 microg/g) than in hatch-year birds (4.61 microg/g). A substantial portion of SFB black rail populations may be at risk of reproductive effects due to MeHg contamination, as 32-78% of feathers and <10% of blood samples exceeded no observed adverse effect levels. Sea level rise and other anthropogenic threats to endemic tidal marsh species such as black rails may be exacerbated by the presence of MeHg. Further study of population demographics and toxicological effects would further elucidate the effects of MeHg contamination on black rail populations in SFB.


Slitrk1-deficient mice display elevated anxiety-like behavior and noradrenergic abnormalities.
Mutations in SLITRK1 are found in patients with Tourette's syndrome and trichotillomania. SLITRK1 encodes a transmembrane protein containing leucine-rich repeats that is produced predominantly in the nervous system. However, the role of this protein is largely unknown, except that it can modulate neurite outgrowth in vitro. To clarify the role of Slitrk1 in vivo, we developed Slitrk1-knockout mice and analyzed their behavioral and neurochemical phenotypes. Slitrk1-deficient mice exhibited elevated anxiety-like behavior in the elevated plus-maze test as well as increased immobility time in forced swimming and tail suspension tests. Neurochemical analysis revealed that Slitrk1-knockout mice had increased levels of norepinephrine and its metabolite 3-methoxy-4-hydroxyphenylglycol. Administration of clonidine, an alpha2-adrenergic agonist that is frequently used to treat patients with Tourette's syndrome, attenuated the anxiety-like behavior of Slitrk1-deficient mice in the elevated plus-maze test. These results lead us to conclude that noradrenergic mechanisms are involved in the behavioral abnormalities of Slitrk1-deficient mice. Elevated anxiety due to Slitrk1 dysfunction may contribute to the pathogenesis of neuropsychiatric diseases such as Tourette's syndrome and trichotillomania.


Effect of Antithrombotic Therapy on Clinical Outcomes in Outpatients With Clinically Stable Symptomatic COVID-19: The ACTIV-4B Randomized Clinical Trial.
Acutely ill inpatients with COVID-19 typically receive antithrombotic therapy, although the risks and benefits of this intervention among outpatients with COVID-19 have not been established. To assess whether anticoagulant or antiplatelet therapy can safely reduce major adverse cardiopulmonary outcomes among symptomatic but clinically stable outpatients with COVID-19. The ACTIV-4B Outpatient Thrombosis Prevention Trial was designed as a minimal-contact, adaptive, randomized, double-blind, placebo-controlled trial to compare anticoagulant and antiplatelet therapy among 7000 symptomatic but clinically stable outpatients with COVID-19. The trial was conducted at 52 US sites between September 2020 and June 2021; final follow-up was August 5, 2021. Prior to initiating treatment, participants were required to have platelet count greater than 100 000/mm3 and estimated glomerular filtration rate greater than 30 mL/min/1.73 m2. Random allocation in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days. The primary end point was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause. The primary analyses for efficacy and bleeding events were limited to participants who took at least 1 dose of trial medication. On June 18, 2021, the trial data and safety monitoring board recommended early termination because of lower than anticipated event rates; at that time, 657 symptomatic outpatients with COVID-19 had been randomized (median age, 54 years [IQR, 46-59]; 59% women). The median times from diagnosis to randomization and from randomization to initiation of study treatment were 7 days and 3 days, respectively. Twenty-two randomized participants (3.3%) were hospitalized for COVID-19 prior to initiating treatment. Among the 558 patients who initiated treatment, the adjudicated primary composite end point occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5-mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group. The risk differences compared with placebo for the primary end point were 0.0% (95% CI not calculable) in the aspirin group, 0.7% (95% CI, -2.1% to 4.1%) in the 2.5-mg apixaban group, and 1.4% (95% CI, -1.5% to 5.0%) in the 5-mg apixaban group. Risk differences compared with placebo for bleeding events were 2.0% (95% CI, -2.7% to 6.8%), 4.5% (95% CI, -0.7% to 10.2%), and 6.9% (95% CI, 1.4% to 12.9%) among participants who initiated therapy in the aspirin, prophylactic apixaban, and therapeutic apixaban groups, respectively, although none were major. Findings inclusive of all randomized patients were similar. Among symptomatic clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome. However, the study was terminated after enrollment of 9% of participants because of an event rate lower than anticipated. ClinicalTrials.gov Identifier: NCT04498273.


Prothrombin Time and Activated Partial Thromboplastin Time Testing: A Comparative Effectiveness Study in a Million-Patient Sample.
A substantial fraction of all American healthcare expenditures are potentially wasted, and practices that are not evidence-based could contribute to such waste. We sought to characterize whether Prothrombin Time (PT) and activated Partial Thromboplastin Time (aPTT) tests of preoperative patients are used in a way unsupported by evidence and potentially wasteful. We evaluated prospectively-collected patient data from 19 major teaching hospitals and 8 hospital-affiliated surgical centers in 7 states (Delaware, Florida, Maryland, Massachusetts, New Jersey, New York, Pennsylvania) and the District of Columbia. A total of 1,053,472 consecutive patients represented every patient admitted for elective surgery from 2009 to 2012 at all 27 settings. A subset of 682,049 patients (64.7%) had one or both tests done and history and physical (H&P) records available for analysis. Unnecessary tests for bleeding risk were defined as: PT tests done on patients with no history of abnormal bleeding, warfarin therapy, vitamin K-dependent clotting factor deficiency, or liver disease; or aPTT tests done on patients with no history of heparin treatment, hemophilia, lupus anticoagulant antibodies, or von Willebrand disease. We assessed the proportion of patients who received PT or aPTT tests who lacked evidence-based reasons for testing. This study sought to bring the availability of big data together with applied comparative effectiveness research. Among preoperative patients, 26.2% received PT tests, and 94.3% of tests were unnecessary, given the absence of findings on H&P. Similarly, 23.3% of preoperative patients received aPTT tests, of which 99.9% were unnecessary. Among patients with no H&P findings suggestive of bleeding risk, 6.6% of PT tests and 7.1% of aPTT tests were either a false positive or a true positive (i.e. indicative of a previously-undiagnosed potential bleeding risk). Both PT and aPTT, designed as diagnostic tests, are apparently used as screening tests. Use of unnecessary screening tests raises concerns for the costs of such testing and the consequences of false positive results.


Suggestive evidence for Darwinian Selection against asparagine-linked glycans of Plasmodium falciparum and Toxoplasma gondii.
We are interested in asparagine-linked glycans (N-glycans) of Plasmodium falciparum and Toxoplasma gondii, because their N-glycan structures have been controversial and because we hypothesize that there might be selection against N-glycans in nucleus-encoded proteins that must pass through the endoplasmic reticulum (ER) prior to threading into the apicoplast. In support of our hypothesis, we observed the following. First, in protists with apicoplasts, there is extensive secondary loss of Alg enzymes that make lipid-linked precursors to N-glycans. Theileria makes no N-glycans, and Plasmodium makes a severely truncated N-glycan precursor composed of one or two GlcNAc residues. Second, secreted proteins of Toxoplasma, which uses its own 10-sugar precursor (Glc(3)Man(5)GlcNAc(2)) and the host 14-sugar precursor (Glc(3)Man(9)GlcNAc(2)) to make N-glycans, have very few sites for N glycosylation, and there is additional selection against N-glycan sites in its apicoplast-targeted proteins. Third, while the GlcNAc-binding Griffonia simplicifolia lectin II labels ER, rhoptries, and surface of plasmodia, there is no apicoplast labeling. Similarly, the antiretroviral lectin cyanovirin-N, which binds to N-glycans of Toxoplasma, labels ER and rhoptries, but there is no apicoplast labeling. We conclude that possible selection against N-glycans in protists with apicoplasts occurs by eliminating N-glycans (Theileria), reducing their length (Plasmodium), or reducing the number of N-glycan sites (Toxoplasma). In addition, occupation of N-glycan sites is markedly reduced in apicoplast proteins versus some secretory proteins in both Plasmodium and Toxoplasma.


Social Work in the Time of COVID-19: A Case Study from the Global South.
This article explores the experiences of social workers at a non-governmental organisation (NGO) involved in disaster responses to COVID-19 in a rural and resource-challenged region of Cambodia. The views of Khmer and international social workers in the NGO were gathered through an internal auditing process utilising survey and structured conversation methods. Key themes related to the importance of prioritising the safety of staff and clients, effective communication methods, responsiveness of case management systems, public health responses and adapting to emerging needs. To ensure responsiveness to future disaster events consideration should be given in strengthening partnerships, ensuring case management systems are effective for current use but able to be adapted in new circumstances, and that preparation incorporates a focus on diversified funding streams and open communication channels between staff and management. These elements will enable social workers to continue their practice, reassured and with the flexibility required in the post-disaster context.


Hunting for sustainability in tropical secondary forests.
The interaction between land-use change and the sustainability of hunting is poorly understood but is critical for sustaining hunted vertebrate populations and a protein supply for the rural poor. We investigated sustainability of hunting in an Amazonian landscape mosaic, where a small human population had access to large areas of both primary and secondary forest. Harvestable production of mammals and birds was calculated from density estimates. We compared production with offtake from three villages and used catch-per-unit-effort as an independent measure of prey abundance. Most species were hunted unsustainably in primary forest, leading to local depletion of the largest primates and birds. The estimated sustainable supply of wild meat was higher for primary (39 kg x km(-2) x yr(-1)) than secondary forest (22 kg x km(-2) x yr(-1)) because four species were absent and three species at low abundance in secondary forests. Production of three disturbance-tolerant mammal species was 3 times higher in secondary than in primary forest, but hunting led to overexploitation of one species. Our data suggest that an average Amazonian smallholder would require > or = 3.1 km2 of secondary regrowth to ensure a sustainable harvest of forest vertebrates. We conclude that secondary forests can sustainably provide only 2% of the required protein intake of Amazonian smallholders and are unlikely to be sufficient for sustainable hunting in other tropical forest regions.


A Meta-Synthesis of Policy Recommendations Regarding Human Mobility in the Context of Climate Change.
Changing mobility patterns combined with changes in the climate present challenges and opportunities for global health, requiring effective, relevant, and humane policy responses. This study used data from a systematic literature review that examined the intersection between climate change, migration, and health. The study aimed to synthesize policy recommendations in the peer-reviewed literature, regarding this type of environmental migration with respect to health, to strengthen the evidence-base. Systematic searches were conducted in four academic databases (PubMed, Ovid Medline, Global Health and Scopus) and Google Scholar for empirical studies published between 1990-2020 that used any study design to investigate migration and health in the context of climate change. Studies underwent a two-stage protocol-based screening process and eligible studies were appraised for quality using a standardized mixed-methods tool. From the initial 2425 hits, 68 articles were appraised for quality and included in the synthesis. Among the policy recommendations, six themes were discernible: (1) avoid the universal promotion of migration as an adaptive response to climate risk; (2) preserve cultural and social ties of mobile populations; (3) enable the participation of migrants in decision-making in sites of relocation and resettlement; (4) strengthen health systems and reduce barriers for migrant access to health care; (5) support and promote optimization of social determinants of migrant health; (6) integrate health into loss and damage assessments related to climate change, and consider immobile and trapped populations. The results call for transformative policies that support the health and wellbeing of people engaging in or affected by mobility responses, including those whose migration decisions and experiences are influenced by climate change, and to establish and develop inclusive migrant healthcare.


Virtual screening of small molecules databases for discovery of novel PARP-1 inhibitors: combination of in silico and in vitro studies.
Poly(ADP-ribose) polymerase-1 (PARP-1) enzyme has critical roles in DNA replication repair and recombination. Thus, PARP-1 inhibitors play an important role in the cancer therapy. In the current study, we have performed combination of in silico and in vitro studies in order to discover novel inhibitors against PARP-1 target. Structure-based virtual screening was carried out for an available small molecules database. A total of 257,951 ligands from Otava database were screened at the binding pocket of PARP-1 using high-throughput virtual screening techniques. Filtered structures based on predicted binding energy results were then used in more sophisticated molecular docking simulations (i.e. Glide/standard precision, Glide/XP, induced fit docking - IFD, and quantum mechanics polarized ligand docking - QPLD). Potential high binding affinity compounds that are predicted by molecular simulations were then tested by in vitro methods. Computationally proposed compounds as PARP-1 inhibitors (Otava Compound Codes: 7111620047 and 7119980926) were confirmed by in vitro studies. In vitro results showed that compounds 7111620047 and 7119980926 have IC50 values of 0.56 and 63 μM against PARP-1 target, respectively. The molecular mechanism analysis, free energy perturbation calculations using long multiple molecular dynamics simulations for the discovered compounds which showed high binding affinity against PARP-1 enzyme, as well as structure-based pharmacophore development (E-pharmacophore) studies were also studied.


A phase I trial of cyclosphosphamide and carboplatinum combined with interleukin-3 in women with advanced-stage ovarian cancer.
The hematopoietic growth factor, recombinant human interleukin-3 (rhu IL-3), stimulates production of both leukocytes and platelets, and thus potentially has greater utility than growth factors that solely stimulate leukocytes production when employed with dose-intensive chemotherapeutic regimens. To determine the optimal schedule for administration of rhu IL-3 in combination with cyclophosphamide and carboplatin, an aggressive regimen for the treatment of advanced ovarian cancer, a phase I trial was initiated by the New York Gynecologic Oncology Group. Following surgical debulking, all patients received cyclophosphamide and carboplatin for 6 cycles. rhu IL-3 was administered at 50, 250, or 500 microgram subcutaneously for 5 days either immediately prior to or after administration of chemotherapy. Cohorts of six patients were treated at each dose level (three pre- and three postchemotherapy). Eighteen patients received 91 cycles of treatment. The major toxicities attributable to rhu IL-3 included fevers, chills, malaise, nausea, and headache, but were not dose-limiting at the doses of rhu IL-3 employed. The major finding of this study was that rhu IL-3 administered after chemotherapy offered greater platelet protection than rhu IL-3 administered prior to chemotherapy as assessed by median platelet nadir and duration of platelet counts < 50,000/mm3. A second major finding was a dose-response relationship for rhu IL-3: the two higher doses employed, 250 and 500 micrograms, offered more effective platelet protection than the lower dose employed, 50 micrograms. rhu IL-3 had no significant effects on leukocyte nadirs or duration of nadirs at any schedule or dose employed. rhu IL-3 may reduced the thrombocytopenia associated with aggressive treatment with cyclophosphamide and carboplatin, although this remains to be confirmed in a randomized, placebo-controlled trial. The effects of rhu IL-3 are dose- and schedule-dependent.


Acute stroke after carotid endarterectomy: time for a paradigm shift? Multicenter experience with emergent carotid artery stenting with or without intracranial tandem occlusion thrombectomy.
Stroke in the immediate postoperative period after carotid endarterectomy is a rare complication. Many centers have begun incorporating angiography before surgical re-exploration, which has the advantage of confirming carotid occlusion and treating tandem intracranial lesions if present. To determine the safety and efficacy of this strategy. A retrospective review was performed of all patients undergoing acute stenting of the carotid artery after carotid endarterectomy from November 2009 to June 2013 at 4 centers. Charts and angiographic images were reviewed. Eleven cases of carotid thrombosis within 72 hours of carotid endarterectomy and subsequent treatment strategies are summarized. All patients had >50% carotid stenosis before carotid endarterectomy. One patient had intraoperative occlusion and dissection of the internal carotid artery, which was noted on intraoperative carotid duplex ultrasound. All patients underwent postoperative computed tomography or computed tomography perfusion scans with subsequent cerebral angiography and stent reconstruction within 11 hours of symptom onset. In all cases, carotid recanalization was successfully completed between 32 and 160 minutes from groin puncture. There were no procedural complications. Four patients had a tandem middle cerebral artery occlusion, 3 of whom underwent successful recanalization. Emergent endovascular evaluation in the setting of acute post--carotid endarterectomy thrombosis is a safe and timely treatment option, with the benefit of detecting and treating embolic intracranial lesions. Immediate angiography and intervention in this rare surgical complication show promising initial results.


Demand curve analysis of marijuana use among persons living with HIV.
Despite medicalization and legalization of marijuana use, factors influencing demand for marijuana among persons living with HIV (PLWH) are incompletely understood. This knowledge gap undermines effective clinical management and policies. This study used demand curve simulation methods to address these issues. Marijuana-using PLWH (N = 119) completed experimental tasks to simulate amount of marijuana purchasing/use across different costs (money or time), and likelihood of reselling marijuana or marijuana therapeutic-use registration card in relation to profits. Additional simulations assessed purchasing of marijuana relative to other drug and non-drug goods. Simulated marijuana use decreased as money and time costs increased. Consumption was greater for participants with more severe Cannabis Use Disorder (CUD) and anxiety, intermediate pain levels, and past 90-day opioid use. Whereas few participants chose to sell their registration card, marijuana resale (diversion) steeply increased with profit. Likelihood of seeking marijuana therapeutic-use certification decreased in relation to registration card money cost, having to visit more physicians to get a signature, and delay to receiving the card, and increased with duration of certification. Participants who reported recent opioid use were more likely to seek certification. Consumption of several commodities assessed was independent of marijuana. Simulated marijuana use was related to participants' clinical profile (CUD, anxiety and pain symptoms, recent opioid use), and unrelated to purchasing other goods. Likelihood of seeking marijuana therapeutic-use registration was affected by several types of costs and recent opioid use. Participants were unlikely to divert registration cards. We discuss clinical and policy implications of these findings.


Simulating forest productivity along a neotropical elevational transect: temperature variation and carbon use efficiency.
A better understanding of the mechanisms controlling the magnitude and sign of carbon components in tropical forest ecosystems is important for reliable estimation of this important regional component of the global carbon cycle. We used the JULES vegetation model to simulate all components of the carbon balance at six sites along an Andes-Amazon transect across Peru and Brazil and compared the results to published field measurements. In the upper montane zone the model predicted a lack of forest vegetation, indicating a need for better parameterization of the responses of cloud forest vegetation within the model. In the lower montane and lowland zones simulated ecosystem productivity and respiration were predicted with reasonable accuracy, although not always within the error bounds of the observations. Model-predicted carbon use efficiency in this transect surprisingly did not increase with elevation, but remained close to the 'temperate' value 0.5. Upper montane forests were predicted to allocate ~50% of carbon fixation to biomass maintenance and growth, despite available measurements showing that they only allocate ~33%. This may be explained by elevational changes in the balance between growth and maintenance respiration within the forest canopy, as controlled by both temperature- and pressure-mediated processes, which is not yet well represented in current vegetation models.


Safety First! Using a Checklist for Intrafacility Transport of Adult Intensive Care Patients.
Adult critical care patients in an academic medical center experienced adverse events during intrafacility transport resulting from lack of preparation. An intervention was needed to help keep patients safe during intrafacility transport. To develop a checklist for transport that is easy to use and effective in preparing patients for transport. A checklist was developed and implemented. Elements of the checklist include preparation of the patient before transport, screening of patients for criteria that may place them at higher risk during transport, and a checklist for the procedural site. From May 2011 through July 2014, 2506 transports were conducted. Of these, 97.6% (n = 2445) involved no reported complications. This tool is suitable for bedside clinicians to use when preparing patients for transport.


Estimating the spatial amplification of damage caused by degradation in the Amazon.
The Amazon rainforests have been undergoing unprecedented levels of human-induced disturbances. In addition to local impacts, such changes are likely to cascade following the eastern-western atmospheric flow generated by trade winds. We propose a model of spatial and temporal interactions created by this flow to estimate the spread of effects from local disturbances to downwind locations along atmospheric trajectories. The spatial component captures cascading effects propagated by neighboring regions, while the temporal component captures the persistence of local disturbances. Importantly, all these network effects can be described by a single matrix, acting as a spatial multiplier that amplifies local forest disturbances. This matrix holds practical implications for policymakers as they can use it to easily map where the damage of an initial forest disturbance is amplified and propagated to. We identify regions that are likely to cause the largest impact throughout the basin and those that are the most vulnerable to shocks caused by remote deforestation. On average, the presence of cascading effects mediated by winds in the Amazon doubles the impact of an initial damage. However, there is heterogeneity in this impact. While damage in some regions does not propagate, in others, amplification can reach 250%. Since we only account for spillovers mediated by winds, our multiplier of 2 should be seen as a lower bound.


Cafestol has a weaker inhibitory effect on osteoclastogenesis than kahweol and promotes osteoblast differentiation.
Bone homeostasis is regulated by a balance between osteoclast (OCL)-mediated bone resorption and osteoblast (OBL)-mediated bone formation. Thus, developing a compound that simultaneously inhibits OCL function and promotes OBL function would be useful as a new medical therapy for bone diseases. Here, we examined the effects of cafestol, a coffee diterpene, on the differentiation of OCLs and OBLs. Cafestol prevented OCL formation in a dose-dependent manner and suppressed the bone-resorbing activity of OCLs. Interestingly, the viability of OCLs treated with 10-50 µM cafestol was significantly higher than that of untreated cells. At the molecular level, cafestol markedly decreased RANKL-induced phosphorylation of extracellular signal-regulated kinase (Erk) and inhibitor of nuclear factor kappa B alpha (IκBα). Compared to kahweol, another coffee-specific diterpene, the inhibitory effects of cafestol were milder on OCL differentiation, and cafestol and kahweol showed different characteristics in induction of the phase ΙΙ antioxidant enzymes and sensitivities in nuclear factor-erythroid 2-related factor 2 (Nrf2)-deficient BMMs. In addition to inhibiting OCLs, cafestol enhanced the differentiation of osteoblastic cells by increasing the mRNA levels of differentiation markers. Thus, cafestol inhibits OCL differentiation and promotes OBL differentiation, suggesting that cafestol may be a novel agent for bone diseases.


Oxidant production and immune response after stretch injury in skeletal muscle.
This study investigated oxidant production and associated immune response after acute muscle stretch injury. A standardized single stretch injury was performed on the tibialis anterior (TA) muscle of 36 male New Zealand white rabbits while contralateral control limbs underwent a sham surgery. Animals were sacrificed 0, 4, 12, 24, 48, and 72 h after injury. Potential sites of oxidant production, measured with a dichlorofluorescein (DCF) probe, were evaluated using two separate buffers. Nonmitochondrial oxidant production measured under basal buffer conditions (0.1 M potassium phosphate) was increased in both injured and control limbs at 24 h (P < 0.01) and was greater in the injured limb at 12 and 48 h (P < 0.01). There was also an interaction of time and injury (P < 0.05). Maximum oxidant production by neutrophils and macrophages, stimulated by the induced buffer (including 1.7 mM ADP, 0.1 mM NADPH, 0.1 mM FeCl3), was increased in both injured and control limbs at 4 h (P < 0.01) and was greater in the injured limb at 48 h (P < 0.01). Myeloperoxidase (MPO) activity, indicating the presence of activated neutrophils, was higher in the injured limb at 4 and 48 h (P < 0.01). The activities of superoxide radical producing and quenching enzymes, xanthine oxidase (XO) and superoxide dismutase (SOD), were elevated at 24 (P < 0.01) and 4 h (P < 0.05), respectively, but showed no difference between injured and control limbs. We conclude that acute muscle stretch injury and the required surgeries to generate the injury result in a biphasic increase in oxidant production in both injured and control limbs, suggesting a systemic immune response. The increase in oxidant production at 4 h may be caused by an increase in activated neutrophils, whereas XO activity may contribute to oxidant generation at 24 h.


Effects of gemfibrozil on low-density lipoprotein particle size, density distribution, and composition in patients with type II diabetes.
To study the effects of gemfibrozil treatment on LDL particle size, density distribution, and composition in NIDDM patients. We performed LDL analyses on 16 NIDDM patients with stable glycemic control. They were randomly allocated to receive either gemfibrozil (n = 8) or a placebo (n = 8) for 3 mo in a double-blind study. The LDL particle size distribution and the particle diameter of the major LDL peak were measured with nondenaturing polyacrylamide gradient gel electrophoresis. The density distribution and composition of LDL were determined with the density gradient ultracentrifugation method. In the gemfibrozil group the mean serum TG concentration decreased by 38%, HDL cholesterol concentration increased by 10%, and LDL cholesterol concentration by 17% (P < 0.05). During gemfibrozil therapy the mean particle diameter of the major LDL peak increased from 244 to 251 A (P < 0.05), whereas in the placebo group the mean LDL particle diameter remained unchanged. We found an inverse correlation between the changes of serum TG and the particle diameters of the major LDL peak (r = 0.85, P < 0.01). Gemfibrozil produced a shift in the LDL density distribution toward lower density. The mean peak density decreased from 1.0371 to 1.0345 g/ml because of a significant rise in the light LDL concentration from 141.0 to 183.2 mg/dl (P < 0.05), whereas the concentration of dense LDL had a tendency to decrease. In the placebo group the LDL density distribution did not change. Gemfibrozil increased the CE-to-TG ratio in LDL core lipids by 27% (P < 0.05); otherwise, the LDL composition was only slightly affected. The results indicate gemfibrozil-induced changes in LDL properties in NIDDM patients are similar to those previously reported in nondiabetic individuals and are related to changes in serum TG level.


Fractional laser photothermolysis for treatment of facial wrinkles in Asians.
To evaluate the safety and efficacy of fractional photothermolysis (FP) in the treatment of facial wrinkles in Asians. A total of 27 Korean patients (Fitzpatrick type III or IV) received 2-3 FP treatment sessions (Sellas; Dinona Inc., Seoul, Korea) spaced two weeks apart. Treatments were performed at settings of 7 to 9 mJ/microthermal treatment zone (MTZ) and a density of 1000 MTZ/cm(2). Standardized digital photographs were obtained before each treatment and three months after the final treatment. The evaluations of clinical photographs were performed by three physicians blinded to the study subjects using a five-point grading scale. In addition, the patients' perceived degree of improvement was assessed three months after the final treatment using a five-point grading scale. Side effects were monitored at each follow-up visit. The physicians' assessed degrees of improvement were excellent in three patients (12%), significant in ten (40%), and moderate in seven (28%). The patients' self-assessed degrees of improvement were excellent in five patients (20%), significant in 11 (44%), and moderate in six (24%). Adverse events were limited to transient pain, erythema and edema, except in one case of transient postinflammatory hyperpigmentation. FP is an effective treatment modality for reducing facial wrinkles with minimal side effects in Asian patients.


Applications of Fourier transform infrared microspectroscopy in studies of benign prostate and prostate cancer. A pilot study.
Fourier transform infrared (FTIR) microspectroscopy has been applied to a study of prostate cancer cell lines derived from different metastatic sites and to tissue from benign prostate and Gleason-graded malignant prostate tissue. Paraffin-embedded tissue samples were analysed by FTIR, after mounting onto a BaF(2) plate and subsequent removal of wax using Citroclear followed by acetone. Cell lines were analysed as aliquots of cell suspension held between two BaF(2) plates. It was found that the ratio of peak areas at 1030 and 1080 cm(-1), corresponding to the glycogen and phosphate vibrations respectively, suggests a potential method for the differentiation of benign from malignant cells. The use of this ratio in association with FTIR spectral imaging provides a basis for estimating areas of malignant tissue within defined regions of a specimen. Initial chemometric treatment of FTIR spectra, using the linear discriminant algorithm, demonstrates a promising method for the classification of benign and malignant tissue and the separation of Gleason-graded CaP spectra. Using the principle component analysis, this study has achieved for the first time the separation of FTIR spectra of prostate cancer cell lines derived from different metastatic sites.


ESR1 polymorphism (rs2234693) influences femoral bone mass in patients with Turner syndrome.
Most patients with Turner syndrome (TS) need hormone replacement therapy because of hypergonadotropic hypogonadism; individual outcomes, however, are highly variable. Our objective was to assess the influence of five estrogen receptor 1 gene (ESR1) polymorphisms (rs543650, rs1038304, rs2046210, rs2234693 and rs9340799) on adult height, breast development, uterine volume and bone mineral density (BMD). We studied 91 TS patients from a tertiary hospital using adult estrogen dose. In our group, ESR1 rs2234693 was associated with femoral neck and total hip BMD, and it accounted for around 10% of BMD variability in both sites (P < 0.01). Patients homozygous for C allele in this polymorphism had significantly lower femoral neck BMD (0.699 ± 0.065 g/cm2 vs 0.822 ± 0.113 g/cm2, P = 0.008) and total hip BMD (0.777 ± 0.118 g/cm2 vs 0.903 ± 0.098 g/cm2, P = 0.009) than patients homozygous for T allele. The other four ESR1 polymorphisms were not able to predict any of the above estrogen therapy outcomes in an isolated manner. Patients homozygous for the haplotype GCG formed by polymorphisms rs543650, rs2234693 and rs9340799 had an even more significantly lower femoral neck BMD (0.666 ± 0.049 vs 0.820 ± 0.105 g/cm2, P = 0.0047) and total hip BMD (0.752 ± 0.093 vs 0.908 ± 0.097 g/cm2, P = 0.0029) than patients homozygous for haplotypes with a T allele in rs2234693. In conclusion, homozygosity for C allele in ESR1 rs2234693 and/or for GCG haplotype appears to be associated with lower femoral neck and total hip BMD. We believe that the identification of polymorphisms related to estrogen outcomes may contribute to individualization of treatment in TS.


Iron-binding activity in yeast frataxin entails a trade off with stability in the alpha1/beta1 acidic ridge region.
Frataxin is a highly conserved mitochondrial protein whose deficiency in humans results in Friedreich's ataxia (FRDA), an autosomal recessive disorder characterized by progressive ataxia and cardiomyopathy. Although its cellular function is still not fully clear, the fact that frataxin plays a crucial role in Fe-S assembly on the scaffold protein Isu is well accepted. In the present paper, we report the characterization of eight frataxin variants having alterations on two putative functional regions: the alpha1/beta1 acidic ridge and the conserved beta-sheet surface. We report that frataxin iron-binding capacity is quite robust: even when five of the most conserved residues from the putative iron-binding region are altered, at least two iron atoms per monomer can be bound, although with decreased affinity. Furthermore, we conclude that the acidic ridge is designed to favour function over stability. The negative charges have a functional role, but at the same time significantly impair frataxin's stability. Removing five of those charges results in a thermal stabilization of approximately 24 degrees C and reduces the inherent conformational plasticity. Alterations on the conserved beta-sheet residues have only a modest impact on the protein stability, highlighting the functional importance of residues 122-124.


Physician decision-making in the management of work related upper extremity injuries.
Physicians working in a tertiary care injured worker clinic are faced with clinical decision-making that must balance the needs of patients and society in managing complex clinical problems that are complicated by the work-workplace context. The purpose of this study is to describe and characterize the decision-making process of upper extremity specialized surgeons when managing injured workers within a specialized worker's compensation clinic. Surgeons were interviewed in a semi-structured manner. Following each interview, the surgeon was also observed in a clinic visit during a new patient assessment, allowing observation of the interactional patterns between surgeon and patient, and comparison of the process described in the interview to what actually occurred during clinic visits. The primary central theme emerging from the surgeon interviews and the clinical observation was the focus on the importance of comprehensive assessment to make the first critical decision: an accurate diagnosis. Two subthemes were also found. The first of these involved the decision whether to proceed to management strategies or to continue with further investigation if the correct diagnosis is uncertain. Once the central theme of diagnosis was achieved, a second subtheme was highlighted; selecting appropriate management options, given the complexities of managing the injured worker, the workplace, and the compensation board. This study illustrates that upper extremity surgeons rely on their training and experience with upper extremity conditions to follow a sequential but iterative decision-making process to provide a more definitive diagnosis and treatment plan for workers with injuries that are often complex. The surgeons are challenged by the context which takes them out of their familiar zone of typical clinical practice to deal with the interactions between the injury, worker, work, workplace and insurer.


Working with Senior Residents: How to get past "You're doing great!"
This content is intended for emergency medicine faculty. Faculty at our institution noted that it can be easy to identify and address the knowledge gaps of junior learners. However, they often find different skills are needed when precepting senior residents, a sentiment shared by faculty at other institutions.1 To foster the skills needed for lifelong learning and deliberate practice, it is crucial that educators find methods to effectively assess the skills of senior residents and provide them with continued feedback.2 The goal of this faculty development session is to outline methods educators can use with senior residents to support their autonomy and independence while exploring their clinical reasoning, pushing them outside of their comfort zone, and promoting reflective and deliberate practice.2-9. By the end of the lecture, all faculty will be able to 1) describe how to use the Aunt Minnie method of precepting for senior residents, 2) list examples of ways in which they can probe the clinical reasoning of senior residents, 3) explain how to use reflective feedback techniques with senior residents, and 4) report use of the techniques discussed during this session when precepting senior residents in the emergency department. This content is presented as a PowerPoint lecture with subsequent discussion. A post-session survey was distributed to allow participants to evaluate the session. This survey was sent four months after the session to gauge how often participants were using the covered techniques on their clinical shifts in the interim. The majority of survey respondents reported that they initially felt that precepting senior learners was "somewhat difficult" and that they found this session "valuable" in helping them address this challenge. Faculty reported using all of the techniques discussed in this session during their clinical shifts, but were more likely to use methods to promote clinical reasoning or reflective feedback than the Aunt Minnie method of precepting. Overall, respondents reported learning new skills during this exercise and appreciated the format which allowed them to share their own experiences of working with the senior residents and brainstorm techniques that might be useful beyond those discussed by the instructors. This faculty development session successfully introduced emergency medicine faculty to techniques that can be used to improve feedback and assessment of senior residents. The lecture format allowed for efficient transmission of material, while several group discussions and a role-play activity allowed for integration of material and sharing of experiences. Overall this exercise was a success with faculty reporting use of several of the techniques discussed. In future iterations, it may be beneficial to integrate more role-play activities to allow participants to practice more of the skills learned in a simulated environment prior to implementing on shifts with learners. Feedback, deliberate practice, clinical reasoning, precepting.


Sp-1 binds promoter elements regulated by the RB protein and Sp-1-mediated transcription is stimulated by RB coexpression.
The retinoblastoma (RB) protein is implicated in transcriptional regulation of at least five cellular genes, including c-fos, c-myc, and transforming growth factor beta 1. Cotransfection of RB and truncated promoter constructs has defined a discrete element (retinoblastoma control element; RCE) within the promoters of each of these genes as being necessary for RB-mediated transcription control. Previously, we have shown that RCEs form protein-DNA complexes in vitro with three heretofore unidentified nuclear proteins and mutation of their DNA-binding site within the c-fos RCE results in an abrogation of RCE-dependent transcription in vivo. Here, we demonstrate that one of the nuclear proteins that binds the c-fos, c-myc, and transforming growth factor beta 1 RCEs in vitro is Sp-1 and that Sp-1 stimulates RCE-dependent transcription in vivo. Moreover, we show that Sp-1-mediated transcription is stimulated by the transient coexpression of RB protein. We conclude from these observations that RB may regulate transcription in part by virtue of its ability to functionally interact with Sp-1.


The sex life of women surviving breast cancer.
The diagnosis of breast cancer elicits diverse emotional responses in patients and partners. Surviving cancer has raised new needs and caretakers must understand the medical and psychological latent effects of oncology therapy. Improving patients' well-being is crucial as 19 million survivors are expected in the next decade in the United States alone. In general, sexuality contributes to one's well-being but when it is disrupted by the occurrence of cancer, women withdraw emotionally, no longer feel desirable due to esthetic damage, and become overwhelmed by the thought of sex. Alopecia and mastectomy elicit feelings of unattractiveness affecting even some women with nipple sparing mastectomy. Couples who share the psychological distress of experiencing cancer should be logically included in survivorship interventions. Hence, any support offered to the couple improves their ability to cope significantly. Treatments causing premature ovarian failure as well as adjuvant endocrine treatments deepen the effects of hypo-estrogenism on the genital modifications of arousal. Sexual rehabilitation with vaginal dilators and sensate focus exercises help to lessen pain, and reduce the couple's anxiety toward sex. In conclusion, caregivers must realize that surviving women are often reluctant to voice their needs, thus, efficient interventions must be available to everyone.


Allelic variation of HERV-K(HML-2) endogenous retroviral elements in human populations.
Human endogenous retroviruses (HERVs) are the remnants of ancient germ cell infection by exogenous retroviruses and occupy up to 8% of the human genome. It has been suggested that HERV sequences have contributed to primate evolution by regulating the expression of cellular genes and mediating chromosome rearrangements. After integration approximately 28 million years ago, members of the HERV-K (HML-2) family have continued to amplify and recombine. To investigate the utility of HML-2 polymorphisms as markers for the study of more recent human evolution, we compiled a list of the structure and integration sites of sequences that are unique to humans and screened each insertion for polymorphism within the human genome databases. Of the total of 74 HML-2 sequences, 18 corresponded to complete or near-complete proviruses, 49 were solitary long terminal repeats (LTRs), 6 were incomplete LTRs, and 1 was a SVA retrotransposon. A number of different allelic configurations were identified including the alternation of a provirus and solitary LTR. We developed polymerase chain reaction-based assays for seven HML-2 loci and screened 109 human DNA samples from Africa, Europe, Asia, and Southeast Asia. Our results indicate that the diversity of HML-2 elements is higher in African than non-African populations, with population differentiation values ranging from 0.6 to 9.8%. These findings denote a recent expansion from Africa. We compare the phylogenetic relationships of HML-2 sequences that are unique to humans and consider whether these elements have played a role in the remodeling of the hominid genome.


The 14;18 translocation in European cases of follicular lymphoma: comparison of Southern blotting and the polymerase chain reaction.
The 14;18 chromosomal translocation is widely recognized as a cytogenetic abnormality associated with follicular lymphomas, but estimates of its frequency in this type of lymphoma vary widely from less than 50% to almost 90%. Furthermore, no extensive data have been published on the frequency of t(14;18) in European cases of follicular lymphoma. Lymph nodes from 51 patients with follicular lymphomas obtained from two European centres (Oxford and Copenhagen) were examined for the presence of this translocation. Southern blotting and the polymerase chain reaction (PCR) were used in 26 cases and the PCR alone in 25 cases (from which only degraded DNA or formalin fixed samples were available). DNA probes capable of detecting rearrangement at both the major and the minor breakpoint regions were employed. We could detect t(14;18) in only 21 out of 51 cases (41%). However, a review of the literature showed that comparable results have been obtained previously using both cytogenetic and molecular biological techniques and our results support the view that the global incidence of t(14;18) in follicular lymphoma is no greater than 70%. Furthermore, this study has indicated that the PCR is a reliable method for identifying t(14;18) when only formalin-fixed paraffin-embedded tissue or degraded DNA is available.


A survey of current consultant practice of treatment of severe ankle sprains in emergency departments in the United Kingdom.
To determine current consultant practice in larger UK emergency departments in the management of severe ankle sprains. Questionnaire study to all UK emergency departments seeing more than 50 000 new patients per year. 70% response rate. Most popular treatment was ice, elevation, Tubigrip, and exercise, each of which was reported as used in most cases by over 70% of respondents. Crutches, early weight bearing, and non-steroidal anti-inflammatory drugs were each reported as used in most cases at over half of responding departments. Physiotherapy was usually only used in selected cases. Rest was usually advised for one to three days (35%). Follow up was only recommended for selected patients. The results of this survey suggest that there is considerable variation in some aspects of the clinical approach (including drug treatment, walking aids, periods of rest) taken to the management of severe ankle sprains in the UK, although in some areas (for example, not routinely immobilising, early weight bearing as pain permits, use of physiotherapy, use of rest, ice, and elevation) there was concordance.


Targeting Chronic Pain in Primary Care Settings by Using Behavioral Health Consultants: Methods of a Randomized Pragmatic Trial.
Manualized cognitive and behavioral therapies are increasingly used in primary care environments to improve nonpharmacological pain management. The Brief Cognitive Behavioral Therapy for Chronic Pain (BCBT-CP) intervention, recently implemented by the Defense Health Agency for use across the military health system, is a modular, primary care-based treatment program delivered by behavioral health consultants integrated into primary care for patients experiencing chronic pain. Although early data suggest that this intervention improves functioning, it is unclear whether the benefits of BCBT-CP are sustained. The purpose of this paper is to describe the methods of a pragmatic clinical trial designed to test the effect of monthly telehealth booster contacts on treatment retention and long-term clinical outcomes for BCBT-CP treatment, as compared with BCBT-CP without a booster, in 716 Defense Health Agency beneficiaries with chronic pain. A randomized pragmatic clinical trial will be used to examine whether telehealth booster contacts improve outcomes associated with BCBT-CP treatments. Monthly booster contacts will reinforce BCBT-CP concepts and the home practice plan. Outcomes will be assessed 3, 6, 12, and 18 months after the first appointment for BCBT-CP. Focus groups will be conducted to assess the usability, perceived effectiveness, and helpfulness of the booster contacts. Most individuals with chronic pain are managed in primary care, but few are offered biopsychosocial approaches to care. This pragmatic brief trial will test whether a pragmatic enhancement to routine clinical care, monthly booster contacts, results in sustained functional changes among patients with chronic pain receiving BCBT-CP in primary care.


Role of Id-2 in the maintenance of a differentiated and noninvasive phenotype in breast cancer cells.
Id proteins are inhibitors of basic helix-loop-helix transcription factors and generally stimulate cell proliferation and inhibit differentiation. We have shown that ectopic expression of Id-1 in murine mammary epithelial cells resulted in loss of differentiation and gain of invasive and proliferative abilities. Moreover, Id-1 was highly expressed in aggressive breast cancer cells in culture and in biopsies from infiltrating carcinomas. In contrast to Id-1, we found that, in vitro and in vivo, Id-2 mRNA and protein were up-regulated as mammary epithelial cells lost proliferative capacity and initiated differentiation. We further determined that this up-regulation of Id-2 was a necessary step toward a fully differentiated phenotype in breast cells. Here we show that one of the components of the extracellular matrix network, laminin, is responsible for the increase in Id-2 expression during differentiation. We also show that Id-2 expression is inversely correlated with the rate of proliferation in murine mammary epithelial cells and that Id-2 is expressed at a higher level in differentiated human breast cancer cells in comparison with very aggressive and metastatic cells. When reintroduced in aggressive breast cancer cells, Id-2 is able to reduce their proliferative and invasive phenotypes and decrease their level of matrix metalloproteinase 9 secretion as well as increase syndecan-1 expression. Moreover, little Id-2 protein expression is detectable in human biopsies from aggressive and invasive carcinomas in comparison with in situ carcinomas. In conclusion, Id-2 expression not only follows a pattern opposite to that of Id-1 during mammary gland development and breast cancer progression but also appears to act as an important protein for the maintenance of a differentiated and noninvasive phenotype in normal and transformed breast cells.


Anisotropic transport in 1T' monolayer MoS2 and its metal interfaces.
The investigation of crystallographic orientation dependent carrier transport in a material could lead to novel electronic devices and circuit applications. Although the out-of-plane carrier transport in layered transition metal dichalcogenides (TMDs) is expected to differ from its normal counterpart, in-plane anisotropy is not so common in such materials. The symmetric honeycomb structure of a semiconducting 2H phase MoS2 crystal limits the in-plane anisotropy. However such possibility in a distorted 1T phase i.e., the 1T' phase of the MoS2 crystal has not yet been explored. Using first principles based quantum transport calculations we demonstrate that, due to the clusterization of "Mo" atoms in 1T' MoS2, the transmission along the zigzag direction is significantly higher than that in the armchair direction. Since the metallic 1T' phase finds application in realizing low resistive metal-MoS2 contacts, we further extend this study to the 1T' MoS2 interface with gold and palladium by developing atomistic models for the optimized metal-1T' MoS2 edge contact geometries. Analysing the transmission spectra and electronic conductance values we show that the metal-zigzag 1T' MoS2 interfaces provide best case results, irrespective of the choice of metal. Moreover, we observe that edge contact geometries with the gold electrodes offer lesser resistances, compared to those with palladium electrodes. Our findings could pave the way for designing high performance phase-engineered MoS2 based electron devices.


Characterization of modified PVDF membrane by gamma irradiation for non-potable water reuse.
Poly(vinylidene fluorine) (PVDF) membranes were grafted by gamma-ray irradiation and were sulfonated by sodium sulfite to modify the surface of the membranes. The characteristics of the modified PVDF membranes were evaluated by the data of Fourier transform infrared (FT-IR), X-ray photoelectron spectroscopy (XPS), field-emission scanning electron microscope (FE-SEM), the contact angle of the membrane surface and the water permeability. From the results of FT-IR, XPS and FE-SEM, it was shown that the modified membranes were successfully grafted by gamma-ray irradiation and were sulfonated. The content of oxygen and sulfur increased with the monomer concentration, while the content of fluorine sharply decreased. The pore size of the modified membranes decreased after gamma-ray irradiation. The contact angle and the water permeability showed that the hydrophilicity of the modified membranes played a role in determining the membrane performance. The feasibility study of the modified PVDF membranes for using non-potable water reuse were carried out using a laboratory-scale microfiltration system. Grey wastewater was used as the influent in the filtration unit, and permeate quality satisfied non-potable water reuse guidelines in the Republic of Korea.


The Nature-Nurture Debate and Public Policy.
The contentious nature-nurture debate in developmental psychology is poised to reach a rapprochement with contemporary concepts of gene-environment interaction, transaction, and fit. Discoveries over the past decade have revealed how neither genes nor the environment offers a sufficient window into human development. Rather, the most important discoveries have come from unearthing the manner in which the environment alters gene expression (and how genes impose limits on environmental effects), how biology and the environment influence each other across time, and how maximizing gene-environment fit leads to optimal outcomes for children. The manner in which these factors operate in tandem should direct future scholarship, practice, and public policy.


Transmission dynamics of the etiological agent of SARS in Hong Kong: impact of public health interventions.
We present an analysis of the first 10 weeks of the severe acute respiratory syndrome (SARS) epidemic in Hong Kong. The epidemic to date has been characterized by two large clusters-initiated by two separate "super-spread" events (SSEs)-and by ongoing community transmission. By fitting a stochastic model to data on 1512 cases, including these clusters, we show that the etiological agent of SARS is moderately transmissible. Excluding SSEs, we estimate that 2.7 secondary infections were generated per case on average at the start of the epidemic, with a substantial contribution from hospital transmission. Transmission rates fell during the epidemic, primarily as a result of reductions in population contact rates and improved hospital infection control, but also because of more rapid hospital attendance by symptomatic individuals. As a result, the epidemic is now in decline, although continued vigilance is necessary for this to be maintained. Restrictions on longer range population movement are shown to be a potentially useful additional control measure in some contexts. We estimate that most currently infected persons are now hospitalized, which highlights the importance of control of nosocomial transmission.


Intersex and alterations in reproductive development of a cichlid, Tilapia guineensis, from a municipal domestic water supply lake (Eleyele) in Southwestern Nigeria.
The objectives of this study were to develop and validate biomarker techniques for aquatic environmental monitoring of endocrine disrupting chemicals (EDCs) in Nigeria aquatic ecosystems, using the Eleyele Lake, which is a major source of domestic water supply to Ibadan and its surrounding towns, as a model aquatic environment and Tilapia guineensis, as a model organism. A total of 55 male and 28 female fish were used for this study. No significant difference in condition factor was observed between the sexes. Evaluation of gross gonadal morphology of the sampled fish showed 33% intersex prevalence in the sampled population, of which respective 71 and 29% were males and females, with visible testis and ovary developing alongside phenotypic females and males. Plasma concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), 11-ketotestosterone (11-KT) and 17β-estradiol (E2) were performed, showing that male fish had significantly higher plasma LH and E2 concentrations, compared to females. Vitellogenin (Vtg) and zona radiata proteins (Zrp) mRNA levels were significantly higher in males, compared to female fish. Contaminant analysis revealed that PCB 81, 123, 138 and 196 were the only PCB congeners detected in sediment and fish muscle (PCB153 in sediment), while dieldrin was the only organochlorine compound (OC) detected in Eleyele sediment. These responses were used in a multivariate analysis, showing that two principal components were extracted and accounted for 74% of total variation in the dataset. The principal component analysis (PCA) showed that male fish variables were positively correlated with PCB congeners 18 and 123, while female fish showed positive correlations with congener 81, 138, 189, 196, indicating sex-specific pattern of association between PCBs concentrations and biomarker expression. In addition, strong positive correlation between male fish and LH, E2, FSH and Vtg was observed, while female fish positively correlated with 11-KT and GSI. These relationships suggest feminization and masculinization of male and female fish, respectively.


Knowledge, attitude and practice of good nutrition among women of childbearing age in Somolu Local Government, Lagos State.
Women of child-bearing age (especially pregnant and lactating women) are in the most nutritionally-vulnerable stages of the life cycle. The aim of this study was to assess the knowledge, attitude and practice of good nutrition among women of childbearing age in Somolu Local Government (LG), Lagos state. This study was a crosssectional descriptive survey of 244 women of childbearing age (15-49 years). Excellent knowledge and good attitude towards good nutrition was observed among 61.89% and 86.89% respectively. During pregnancy, greater than 80% took folic acid, iron supplements and increased daily consumption of fruits and vegetables while 43.59% avoided eggs, fish, meat and chocolate beverage because of taboos. Seven days prior to interview, over 90% had consumed fast foods, 56.15% and 50.01% of the respondents ate fruits and vegetables every day to ≥4 times in a day respectively. A majority of the respondents knew and had a good attitude towards good nutrition supporting studies from Kenya and Northern Nigeria. This, however, did not translate to good practice for about half of the respondents.


"She is my teacher and if it was not for her I would be dead": exploration of rural South African community health workers' information, education and communication activities.
Community health workers (CHWs) are important resources in health systems affected by the HIV/AIDS pandemic. International guidelines on task-shifting recommend that CHWs can provide diverse HIV services, ranging from HIV prevention to counselling patients for lifelong antiretroviral therapy. There is, however, little evidence on the experiences with CHW delivery of these services in Africa. This qualitative study included 102 interviews that explored experiences with information, education and communication (IEC) activities provided by CHWs within rural South Africa. Semi-structured interviews were conducted with CHWs (n = 17), their clients (n = 33) and the primary caregivers of these clients (n = 30), allowing for data source triangulation. Twenty-two follow-up interviews explored emergent themes from preliminary interviews. Despite limited formal education and training, CHWs in this study were significant providers of IEC, including provision of generic health talks and HIV-specific information and facilitation to support clients' entry and maintenance in the formal health system. They often incorporated local knowledge and understanding of illness in their communication. CHWs in this study were able to bridge the lifeworlds of the community and the formal services to expedite access and adherence to local clinics and other services. As mediators between the two worlds, CHWs reinterpreted health information to make it comprehensible in their communities. With growing formalisation of CHW programmes in South Africa and elsewhere, CHWs' important role in health service access, health promotion and health maintenance must be recognised and supported in order to maximise impact.


Whole grain, bran, and germ intake and risk of type 2 diabetes: a prospective cohort study and systematic review.
Control of body weight by balancing energy intake and energy expenditure is of major importance for the prevention of type 2 diabetes, but the role of specific dietary factors in the etiology of type 2 diabetes is less well established. We evaluated intakes of whole grain, bran, and germ in relation to risk of type 2 diabetes in prospective cohort studies. We followed 161,737 US women of the Nurses' Health Studies (NHSs) I and II, without history of diabetes, cardiovascular disease, or cancer at baseline. The age at baseline was 37-65 y for NHSI and 26-46 y for NHSII. Dietary intakes and potential confounders were assessed with regularly administered questionnaires. We documented 6,486 cases of type 2 diabetes during 12-18 y of follow-up. Other prospective cohort studies on whole grain intake and risk of type 2 diabetes were identified in searches of MEDLINE and EMBASE up to January 2007, and data were independently extracted by two reviewers. The median whole grain intake in the lowest and highest quintile of intake was, respectively, 3.7 and 31.2 g/d for NHSI and 6.2 and 39.9 g/d for NHSII. After adjustment for potential confounders, the relative risks (RRs) for the highest as compared with the lowest quintile of whole grain intake was 0.63 (95% confidence interval [CI] 0.57-0.69) for NHSI and 0.68 (95% CI 0.57-0.81) for NHSII (both: p-value, test for trend <0.001). After further adjustment for body mass index (BMI), these RRs were 0.75 (95% CI 0.68-0.83; p-value, test for trend <0.001) and 0.86 (95% CI 0.72-1.02; p-value, test for trend 0.03) respectively. Associations for bran intake were similar to those for total whole grain intake, whereas no significant association was observed for germ intake after adjustment for bran. Based on pooled data for six cohort studies including 286,125 participants and 10,944 cases of type 2 diabetes, a two-serving-per-day increment in whole grain consumption was associated with a 21% (95% CI 13%-28%) decrease in risk of type 2 diabetes after adjustment for potential confounders and BMI. Whole grain intake is inversely associated with risk of type 2 diabetes, and this association is stronger for bran than for germ. Findings from prospective cohort studies consistently support increasing whole grain consumption for the prevention of type 2 diabetes.


Mutations in the HPV16 genome induced by APOBEC3 are associated with viral clearance.
HPV16 causes half of cervical cancers worldwide; for unknown reasons, most infections resolve within two years. Here, we analyze the viral genomes of 5,328 HPV16-positive case-control samples to investigate mutational signatures and the role of human APOBEC3-induced mutations in viral clearance and cervical carcinogenesis. We identify four de novo mutational signatures, one of which matches the COSMIC APOBEC-associated signature 2. The viral genomes of the precancer/cancer cases are less likely to contain within-host somatic HPV16 APOBEC3-induced mutations (Fisher's exact test, P = 6.2 x 10-14), and have a 30% lower nonsynonymous APOBEC3 mutation burden compared to controls. We replicate the low prevalence of HPV16 APOBEC3-induced mutations in 1,749 additional cases. APOBEC3 mutations also historically contribute to the evolution of HPV16 lineages. We demonstrate that cervical infections with a greater burden of somatic HPV16 APOBEC3-induced mutations are more likely to be benign or subsequently clear, suggesting they may reduce persistence, and thus progression, within the host.


Pre-pubertal and adolescent germ cell neoplasms in Taiwan: time trends and geographic variation.
Evidence from our previous study suggested that the incidence of germ cell neoplasms in children and adolescents is increasing. The objectives of this analysis were to quantify this trend in patients aged 0-9 and 10-19 years (pre-pubertal and adolescent groups, respectively) and compare rates in Taiwan according to geographic distribution. Germ cell neoplasm frequencies among 1267 patients aged 0-19 years spanning 1995-2009 were obtained from the population-based Taiwan Cancer Registry. The incidence patterns according to sex, age, disease subgroup, and geographic distribution were analyzed. The incidence rates in the pre-pubertal and adolescent groups were 10.58 and 16.06 per million person-years, respectively. The overall rates increased significantly by 3.2% annually in the adolescent group during the 15-year study period, and increased only among the males. In contrast, no change in trend was observed in the pre-pubertal group. Subgroup analysis showed significant upward trends in the incidence rates of intracranial/intraspinal and testicular germ cell tumors (GCTs) in the adolescent males and extracranial/extragonadal GCTs in the pre-pubertal boys. The most striking differences between the study population and white Americans were that the rates of testicular GCTs were 5-fold higher and 4-fold lower in the Taiwanese pre-pubertal and adolescent groups, respectively. Significantly higher rates were found in Hualien and Chiayi Counties compared with the other areas of Taiwan. The upward trend of testicular GCTs in the adolescent males is consistent with findings from Western countries. The underlying causes that led to the high rate of testicular GCTs in the pre-pubertal boys and significantly higher rates in specific counties warrant further investigation.


Impairment of adrenergic-induced proopiomelanocortin-related peptide release in heroin addicts.
The effects of iv stimulation with clonidine on plasma levels of beta-lipotropin (beta-LPH), beta-endorphin (beta-EP), cortisol, growth hormone (GH) and adrenocorticotrophic hormone (ACTH) were tested in a group of 10 healthy volunteers and in 8 heroin abusers. Hormones were measured either by direct radioimmunoassay (RIA) (GH, cortisol) or after plasma extraction and Sephadex G-75 column chromatography (beta-LPH and beta-EP) or by immunoradiometric assay (IRMA) (ACTH). Plasma levels of GH increased in a similar fashion in the two groups. In the controls, clonidine induced release of beta-LPH and beta-EP after 30 min (from 8.9 +/- 1.0 to 19.1 +/- 4.6 fmol/ml, P less than 0.01 and from 8.1 +/- 0.6 to 17.9 +/- 4.6, P less than 0.01) and of ACTH after 60 min (from 12.1 +/- 1.8 to 18.1 +/- 1.8, P less than 0.05) while in addicts beta-EP but not beta-LPH showed a significant increase (from 8.5 +/- 0.7 to 19.8 +/- 4.2, P less than 0.05), 90 min after the injection. In heroin addicts, plasma cortisol levels decreased continuously after clonidine stimulation while in controls they showed a biphasic pattern, decreasing until the 60th min (from 135.2 +/- 30.4 ng/ml to 74.0 +/- 13.3, P less than 0.05) and regaining basal levels 1 h later (122.0 +/- 24.8, P less than 0.05 vs 60th min value). These data demonstrate the existence in human beings of noradrenergic control of proopiomelanocortin (POMC)-related peptides and indicate that chronic opiate abuse greatly interferes with this control. Clonidine-induced release of plasma beta-EP may be of importance with regard to its therapeutic effects in detoxification.